PROJECT SUMMARY/ABSTRACT In response to PA-17-303, this Phase I STTR proposal will aim at developing pharmacotherapies that can act as ?life-saver? medications to counteract the neurotoxic effects of synthetic cannabinoids (SCs). Towards this goal, we will synthesize CB1R antagonists with fast-onsets of action that can be administered in an emergency room (ER) situation. The rationale is based on the successful soft-agonist controlled deactivation approach developed at the Northeastern University?s (NEU) Center for Drug Discovery (CDD). The newly discovered ligands will be devoid of the undesirable effects caused by known CB1 inverse-agonists due to their ability to undergo rapid deactivation into inactive metabolites. Given that patients? drug histories may not be known at admission, a key desired characteristic of the proposed antagonists as compared to the well-studied CB1 inverse agonist rimonabant (SR) is that they do not induce prolonged withdrawal reactions. First-generation SCs act as full CB1R agonists, mimic the ?marijuana high? effects of ?9-tetrahydrocannabinol (?9-THC), and exert their psychotropic effects with increased CB1 potency via CB1R activation. SCs are illegally sold as ?designer drugs? and their consumption can be fatal unlike ?9-THC which is a partial agonist and is less toxic. Lately, there has been a dramatic increase in SC related visits to emergency rooms and calls to poison control centers across the USA. Aim 1 will focus on the design and synthesis of novel controlled deactivation CB1R antagonists by utilizing the human CB1R (hCB1) crystal structure that was recently determined by our group. The design encompasses prototypes that have helped establish proof-of-concept. Aim 2 will focus on the in vitro characterization of ligands to determine their hCB1 affinity, hCB1/hCB2 selectivity, functional behavior, and stability. Aim 3 will focus on identifying brain penetrant compounds wherein ligands will be tested for CB1 antagonism and for their side-effects using procedures that are highly reproducible in mice of both genders. Fulfilling Phase I goals will further establish proof-of-concept for providing such treatment and for identifying advanced druggable leads. The project will help transition the most successful compounds towards Phase II for further optimization and pre-clinical evaluation aimed at obtaining one candidate and 2-3 back-ups. The next phase of this grant will focus on testing the optimized leads in validated pre-clinical rodent models of SC induced neurotoxicity using established behavioral paradigms that are considered perfect translational models to humans. Phase II/III development of the most favorable compounds will aim towards IND-enabling studies while partnering with industry.